The Suzuki-Miyaura reaction is a palladium- or nickel-catalyzed cross coupling between a boronic acid or a boronic ester, and an organohalide or an organo-pseudohalide. (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483) This cross coupling transformation is a powerful method for C—C bond formation in complex molecule synthesis. The reaction is tolerant of functional groups, and has become increasingly general and widespread in its use for coupling of organic compounds. (Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685-4696; Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358-3366; Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-4028.; Nicolaou, K. C., et al. Angew. Chem. Int. Ed. 2005, 44, 4442) A difficult aspect of the Suzuki-Miyaura reaction is the sensitivity of the boronic acid functional group to many common reagent, which makes the synthesis of structurally complex organoboronic acid building blocks challenging. (Hall, D. G. Boronic Acids, Wiley-VCH, Germany, 2005, 3-14; Tyrell, 2003)
One area of research on the Suzuki-Miyaura reaction is the development of protecting groups for the boronic acid functional group. In one example of a boronic acid protecting group, each of the two B—OH groups is converted into a boronic ester group (>B—O—R) or a boronic amide group (>B—NH—R), where R is an organic group. (Deng, X.; Mayeux, A.; Cai, C. J. Org. Chem. 2002, 67, 5279-5283; Hohn, E.; Pietruszka, J. Adv. Synth. Catal. 2004, 346, 863-866; Holmes, D., et al. Org. Lett. 2006, 8, 1407-1410; Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem. Soc. 2007, 129, 758-759) The heteroatom-boron bonds in these protected compounds tend to be very strong, however, and the relatively harsh conditions required for cleaving these ligands to provide the free boronic acid group typically are incompatible with complex molecule synthesis. In another example, three organoboronic acid molecules can be condensed to form a cyclic boroxine protecting group. (Kerins, F.; O'Shea, D. F. J. Org. Chem. 2002, 67, 4968-4971) These protected organoboronic acids, however, tend to be unstable to long term storage. The reactivity of a boronic acid group also may be decreased by conversion of the boronic acid group into a tetracoordinate anion, such as [R—BF3]−, where R represents an organic group, as a salt with a counterion such as K+ or Na+. (Molander, G. A; Ellis, N. Acc. Chem. Res. 2007, 40, 275-286) Another class of tetracoordinate boron anions, [R—B(OH)3]−, has been reported in the context of purifying organoboronic acids for use in the Suzuki-Miyaura reaction. (Cammidge, A. N. et al. Organic Letters 2006, 8, 4071-4074) In each of these systems, the boron itself is not protected from the Suzuki-Miyaura reaction, but can be used directly in the coupling transformation.
The most useful and versatile system for protecting boronic acids is the use of an imino-di-carboxylic acid boronate protecting group. Imino-di-carboxylic acid boronates, such as N-methyliminodiacetic acid (MIDA), can be used to protect boronic acid functional groups from a variety of chemical reactions. (U.S. Pat. App. Pub. 2009/0030238; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716-6717; Lee, S. J., Gray, K. C., Paek, J. S., Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466-468) The MIDA boronates are stable to air and to purification by chromatography, and do not cross-couple under anhydrous conditions. However, the protecting group can be hydrolyzed with aqueous base to release the corresponding unprotected organoboronic acid. Thus, MIDA boronates can be used as convenient surrogates for organoboronic acids under aqueous base-promoted Suzuki-Miyaura coupling conditions, and the deprotection and cross-coupling may be performed as a single step in the presence of aqueous base. This approach has been shown to be effective for a wide variety of organoboronic acids.
The base used to simultaneously deprotect the MIDA boronate and promote the cross-coupling reaction may be a mild base. Deprotection of MIDA boronates with a mild base can provide a slower release of the unprotected organoboronic acid into the reaction mixture than that provided through deprotection with a strong base. This slower release can allow cross-coupling to occur between an organohalide or an organo-pseudohalide and an organoboronic acid that would otherwise degrade during the reaction. This slower release also can allow cross-coupling to occur with organoboronic acids that cannot be prepared or isolated in pure form. The method of deprotecting and cross-coupling with a mild base is described, for example, in copending U.S. patent application Ser. No. 12/567,443, entitled “Slow Release of Organoboronic Acids In Cross-Coupling Reactions”, with inventors Martin D. Burke et al., which is incorporated herein by reference.
A challenge that remains in the MIDA protecting system is the formation of protected organoboronic acid building blocks for use in synthesis of complex organic compounds. It would be desirable to provide a wide variety of building blocks, and particularly to provide building blocks containing complex and/or pharmaceutically important structures. It also would be desirable to provide a method of forming simple or complex protected organoboronic acid building blocks that is more straightforward, scalable, and cost-effective.
Regarding the formation of building blocks containing complex and/or pharmaceutically important structures, one such class of structures is the 2-heterocyclic groups. Many pharmaceuticals contain 2-heterocyclic subunits, with 2-pyridyl, 2-furan, 2-thiophene, 2-indole, 2-oxazole, and 2-thiazole being among the most common. These same substructures are also prevalent in natural products, particularly those derived from NRPS and hybrid PKS/NRPS biosynthesis pathways. 2-Substituted heterocycles also commonly appear in probe reagents for chemical biological studies, metal-complexing ligands, and a variety of materials for molecular electronic, display, energy capture, energy storage, and field effect transistor devices.
Although they are among the most desirable synthetic building blocks with respect to low cost, minimal environmental impact, and lack of toxicity, 2-heterocyclic boronic acids are notoriously unstable, which often precludes their effective utilization. Many different types of surrogates have been developed, including trifluoroborate salts, trialkoxy or trihydroxyborate salts, diethanolamine adducts, sterically bulky boronic esters and boroxines. Advances in the development of 2-heterocyclic silanolates have also recently been reported. However, it remains a challenge to develop air-stable, chemically pure, and highly effective surrogates for some of the most challenging classes of 2-heterocyclic building blocks, e.g., the notoriously unstable 2-pyridyl derivatives. 2-heterocyclic stannanes represent stable and effective alternatives, but these reagents suffer from substantial toxicity.
A variety of 2-heterocyclic MIDA boronates have been used successfully in cross-coupling reactions. (U.S. patent application Ser. No. 12/567,443) The 2-heterocyclic MIDA boronate building blocks were not formed by reaction of MIDA with the corresponding unprotected boronic acids, however, as the unprotected boronic acids are notoriously unstable. While alternative methods have been used to form MIDA boronates of boronic acids that would be unstable if unprotected, these methods have met with mixed success. In particular, formation of 2-heterocyclic MIDA boronates containing nitrogen at the 2-position in the heterocyclic group have been cumbersome and low yielding, and have not shown characteristics of scalability. For example, the formation of 2-pyridyl MIDA boronate by reaction of lithium 2-pyridyl-triisopropylboronate with MIDA in DMSO at 75° C. provided only a 27% yield. Thus, it would be desirable to provide an improved method for forming MIDA boronates containing complex and/or pharmaceutically important structures.
Regarding the formation of simple or complex protected organoboronic acid building blocks in a manner that is more straightforward, scalable, and cost-effective, many MIDA boronates can be prepared by refluxing a mixture of the corresponding boronic acid and MIDA in toluene and DMSO in a Dean-Stark apparatus. The DMSO conventionally has been required to partially dissolve the highly polar MIDA reagent. Refluxing in a Dean-Stark apparatus conventionally has been necessary to remove the water that is generated during the complexation process. This conventional method presents a number of challenges, however. Some boronic acids can undergo thermal decomposition at the elevated temperatures of refluxing DMSO, resulting in decreased yields of the MIDA boronate. Moreover, the MIDA reagent can cause the reaction conditions to be acidic, which can be detrimental to acid-sensitive boronic acids. Finally, the DMSO used in the reaction can be challenging to completely remove from the MIDA boronate product.
For example, in the preparation of 5-bromopentanyl MIDA boronate from 5-bromopentanyl boronic acid using the conventional Dean-Stark conditions (PhMe:DMSO 10:1), the 5-bromopentanyl boronic acid substantially decomposed, resulting in low yields of 5-bromopentanyl MIDA boronate. Moreover, the reaction product included residual DMSO, which was difficult to remove.
The number of commercially available boronic acids currently is over 3,000. Moreover, methods for making many other boronic acids are well-known. Thus, it would be desirable to provide a simple and efficient process to transform directly any boronic acid into the corresponding MIDA boronate.